title: Selective inhibition of a regulatory subunit of protein phosphatase 1 restores proteostasis.
abstract: Many biological processes are regulated through the selective dephosphorylation of proteins. Protein serine-threonine phosphatases are assembled from catalytic subunits bound to diverse regulatory subunits that provide substrate specificity and subcellular localization. We describe a small molecule, guanabenz, that bound to a regulatory subunit of protein phosphatase 1, PPP1R15A/GADD34, selectively disrupting the stress-induced dephosphorylation of the α subunit of translation initiation factor 2 (eIF2α). Without affecting the related PPP1R15B-phosphatase complex and constitutive protein synthesis, guanabenz prolonged eIF2α phosphorylation in human stressed cells, adjusting the protein production rates to levels manageable by available chaperones. This favored protein folding and thereby rescued cells from protein misfolding stress. Thus, regulatory subunits of phosphatases are drug targets, a property used here to restore proteostasis in stressed cells.
authors.affiliation: MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, UK.
authors.forename: Pavel
authors.initials: P
authors.lastname: Tsaytler
authors.forename: Heather P
authors.initials: HP
authors.lastname: Harding
authors.forename: David
authors.initials: D
authors.lastname: Ron
authors.forename: Anne
authors.initials: A
authors.lastname: Bertolotti
mesh_terms: D058647:Adrenergic alpha-2 Receptor Agonists / Q000494:pharmacology*; D020134:Catalytic Domain / Q000187:drug effects; D002460:Cell Line; D003000:Clonidine / Q000494:pharmacology; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D006143:Guanabenz / Q000494:pharmacology*; D006367:HeLa Cells; D006706:Homeostasis; D006801:Humans; D018832:Molecular Chaperones / Q000378:metabolism; D010766:Phosphorylation; D014176:Protein Biosynthesis / Q000187:drug effects; D017510:Protein Folding / Q000187:drug effects; D054645:Protein Phosphatase 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D021122:Protein Subunits / Q000187:drug effects / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D013312:Stress, Physiological; D014415:Tunicamycin
chemical_list: D058647:Adrenergic alpha-2 Receptor Agonists; D004791:Enzyme Inhibitors; D015852:Eukaryotic Initiation Factor-2; D018832:Molecular Chaperones; D021122:Protein Subunits; D011506:Proteins; D014415:Tunicamycin; C087519:PPP1R15A protein, human; D054645:Protein Phosphatase 1; D006143:Guanabenz; D003000:Clonidine